tbuckley/cabot-search huggingface dataset:
Abstract 103: Dissecting cell state diversity during melanoma growth and metastasis
Authors: Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Jia Hui Khoo, Dennis Pedri, Anil Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin Simons, Florian Rambow, Jean Christophe Marine
Journal: Cancer Research (2023)

Abstract Cellular plasticity endows cancer cells with capacity towards a phenotypic state. Except from the genetic origin of cellular plasticity, cancer cells can transit to reversible phenotypic states as a result of microenvironmental cues and are often driven by stochastic epigenetic and/or transcriptional fluctuations. Melanoma is a prime example of heterogeneous and plastic tumors where the origin and magnitude of cell state diversity remains poorly understood. Combining lineage tracing, 3D imaging and quantitative mathematical modelling in a clinically-relevant mouse model of melanoma, we demonstrated that tumors follow a hierarchical model of growth supported by a population of Melanoma Stem-like Cells (MSCs) that exhibit a transcriptomic signature of pre-migratory neural crest cells established transiently during embryonic development. ScRNA seq in mouse and drug naïve human biopsies revealed that MSCs are evolutionarily conserved and independent of the “genetic makeup” of the tumors. By deploying spatial transcriptomic approaches and multiplex imaging, we developed a spatially and temporally resolved map of the diversity of melanoma showing a non-random tumor organization. Multimodal analysis unraveled unique cell type and state interactions and importantly demonstrated that MSCs reside in perivascular niches favoring tumor growth. Endothelial Cells were found to have a key role in the acquisition of stemness properties. Co-culture assays led to melanoma dedifferentiation and proliferation advantage. Of note, supplementing melanoma cells with ECs accelerated the growth of tumors in vivo, where MSCs pool was increased. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells harboring a mesenchymal-like state revealed that these cells do not contribute to primary tumor growth but, instead, constitutes a pool of metastatic-initiating cells that switch cell identity while disseminating to secondary organs. Taken together, these results will pave the way for the development of strategies that exploit the “chameleonic” nature of cancer cells and, ultimately, target MSC niche-dependent specification mechanisms. Citation Format: Panagiotis Karras, Ignacio Bordeu, Joanna Pozniak, Ada Nowosad, Cecilia Pazzi, Nina Van Raemdonck, Jia Hui Khoo, Dennis Pedri, Anil Rustgi, Oliver Bechter, Cedric Blanpain, Benjamin Simons, Florian Rambow, Jean Christophe Marine. Dissecting cell state diversity during melanoma growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 103.
Abstract 28: <i>In vivo</i>screening platform based on Ba&amp;lt;/&amp;gt;F3 kinase engineered cell lines for discovery of next-generation kinase inhibitors
Authors: Tongtong Liu, Feng He, Xuyang Duan, shuliang Li, Chang Liu, Jinying Ning, Feng Hao
Journal: Cancer Research (2023)

Abstract Protein kinases have become very popular targets for cancer and other diseases therapy, with more than 70 kinase inhibitor drugs approved by FDA since 2001. Due to innate or acquired drug resistance of tumors, most of these small-molecule inhibitors can only delay tumor progression. Next-generation kinase inhibitors with better specificity and lower drug resistance remain to be developed. Ba/F3 is a mouse pro-B cell line which is dependent on IL-3 for survival and proliferation. Upon transduction of a driver gene such as kinase genes or their mutants, Ba/F3 cells switch from IL3-dependent to driver gene-dependent, which makes Ba/F3 cells a powerful tool for the discovery of new kinase inhibitors. Our group has constructed more than 500 Ba/F3 engineered cell lines stably transfected with mutants of kinase genes. These Ba/F3 kinase cell lines are well validated by sequencing, western blot and inhibitor test, and cover many hot kinases, including EGFR (151 cell lines), FGFR (45 cell lines), ERBB2 (38 cell lines), KRAS (36 cell lines), BCR-ABL (36 cell lines), EML4-ALK (33 cell lines), KIF5B-RET (30 cell lines), FLT3 (26 cell lines) et.al. Most of these transformed Ba/F3 cell lines can be used in allograft models in immune-deficient mice. Based on these Ba/F3 kinase cell line allograft models, we established an in vivo screening platform to evaluate the efficacy and toxicity of drug candidatestargeting specific mutant types of kinases, as well as comparisons with previous generation drugs. Overall, our data indicate that Ba/F3 kinase cell line-derived allograft models are a powerful model for the discovery of next-generation kinase inhibitors. Citation Format: Tongtong Liu, Feng He, Xuyang Duan, shuliang Li, Chang Liu, Jinying Ning, Feng Hao. In vivoscreening platform based on Ba&amp;lt;/&amp;gt;F3 kinase engineered cell lines for discovery of next-generation kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 28.
Abstract 1809: ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality
Authors: Sébastien Jeay, Stefan Diethelm, Agnes Knopf, Marie Goxe, Marie Daugan, Julie Erupathil, Julien Pothier, Davide Pozzi, Thierry Sifferlen, Lorenza Wyder, Isabelle Lyothier, Olivier Corminboeuf, Francois Lehembre, Imke Renz, Dominique Meyer
Journal: Cancer Research (2023)

Abstract Prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors, of which both EP2 and EP4 are abundantly expressed by tumor-infiltrating immune cells including DCs, NK cells, Tregs, cytotoxic T cells and TAMs. Signaling via EP2 and EP4 is immunosuppressive, preventing the mounting of effective anti-tumor immune responses leading to tumor immune escape and tumor progression. Currently, several EP4 selective antagonists and an EP2/4 dual antagonist are being developed for anti-cancer immunotherapy. Using a combination of EP2 and EP4 selective antagonists in different tumor mouse models, we could demonstrate that dual EP2/EP4 blockade is more effectively activating anti-tumor immunity compared to targeting either receptor alone. The concurrent inhibition of EP2 and EP4 resulted in tumor regression and induction of immunological memory. Together with published data showing similar findings, our results suggest that simultaneous targeting of EP2 and EP4 could be a promising new therapeutic approach to overcome cancer immune evasion. Idorsia Pharmaceuticals has identified ACT-1002-4391 as a novel, potent antagonist of EP2 and EP4 receptors with an excellent duality profile. In vitro, ACT-1002-4391 is capable of modulating immune cell proliferation and/or function and is superior to EP2 or EP4 selective inhibition in that respect. In vivo, ACT-1002-4391 displays strong and dose-dependent single agent anti-tumor efficacy in a syngeneic mouse tumor model. Based on the excellent selectivity and duality profile, ACT-1002-4391 will be advanced into clinical development by Idorsia Pharmaceuticals. Citation Format: Sébastien Jeay, Stefan Diethelm, Agnes Knopf, Marie Goxe, Marie Daugan, Julie Erupathil, Julien Pothier, Davide Pozzi, Thierry Sifferlen, Lorenza Wyder, Isabelle Lyothier, Olivier Corminboeuf, Francois Lehembre, Imke Renz, Dominique Meyer. ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1809.
Abstract 3841: Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation
Authors: Graham P. Marsh, Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple
Journal: Cancer Research (2023)

Abstract CREB-binding protein (CBP, CREBBP, KAT3A) and E1A-binding protein (EP300, p300, KAT3B) are paralogous multi-domain proteins that act as chromatin regulators and transcriptional co-activators. They contain a histone acetyltransferase (HAT) domain that catalyzes the histone H3, lysine 27 acetylation (H3K27ac) mark at regulatory elements such as enhancers and promoters. Transcription factors associate with stretches of H3K27ac marks (known as ‘super-enhancer’ elements) and result in gene transcription that ultimately establishes cell identity and fate. They are implicated in cancer pathology, and small molecule inhibition of the bromodomain (BRD) or HAT domain of CBP/p300 are considered promising therapeutic strategies for a number of cancer types. CBP and p300 are highly homologous but have distinct roles that have to date been hard to delineate, since small molecule inhibitors developed to date are unable to selectively target each protein independently. Additionally, small molecule inhibitors that target individual domains are unable to entirely abrogate the full functionality of CBP/p300. A bromodomain-recruiting dual CBP/p300 PROTAC Degrader ‘dCBP1’ was therefore recently developed to provide a chemical tool to explore the phenotypic consequences of CBP/p300 chemical knockdown. A further study demonstrated that it is possible to degrade p300 with some selectivity by converting a CBP/p300 dual HAT-domain inhibitor into a PROTAC, called ‘JQAD1’. We have used a different HAT-domain recruiting ligand to develop novel PROTACs that elicit proteasome-mediated degradation of p300 with significantly enhanced selectivity over CBP, compared with JQAD1. We additionally demonstrate a faster onset of degradation for lead PROTAC molecules and present data exploring the consequences of selective p300 degradation in CIC-DIX4 sarcoma. Citation Format: Graham P. Marsh, Sean Goggins, Darko Bosnakovski, Michael Kyba, Samuel Ojeda, Drew A. Harrison, Christopher J. Ott, Hannah J. Maple. Development of p300-targeting PROTAC degraders with enhanced selectivity and onset of degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3841.
Abstract 382: Synergistic anti-tumor effect of ABN401 in combination with KRAS inhibitor in a c-MET-altered KRASG12C non-small cell lung cancer model
Authors: Saehyung Lee, Sunghwan Cho, Na Young Kim, Rajasekaran Nirmal, Kyung Eui Park, Jun Young Choi
Journal: Cancer Research (2023)

Abstract ABN401, a highly selective c-MET inhibitor, is being evaluated for the treatment of non-small cell lung cancer (NSCLC) in clinical trials. NSCLC is a heterogeneous in nature and leading cause in cancer related mortality. Numerous studies are still ongoing to identify the key oncogenic mutations that promote tumor progression. Various actionable genetic mutations such as EGFR, ALK, BRAF, MET, RET, and NTRK/ROS1 have been identified, and the targeted therapies are being developed. It is known that targeted therapies can control disease progression in NSCLC patients and drug resistance due to their heterogeneity remains a clinical hurdle. Among the targets, KRAS gene mutations, an unactionable and is now considered a promising therapeutic approach for NSCLC. Currently, co-occurrence of KRASG12C mutation has been reported in NSCLC patients with MET alterations. Moreover, oncogenic KRAS protein can induce c-MET expression levels by signaling pathways. In this study, we aim to provide an alternative therapeutic strategy for NSCLC patients with KRASG12C mutation harboring MET alterations. We have performed several in vitro and in vivo efficacy studies for the combination of ABN401, c-MET inhibitor, and sotorasib, KRASG12C variant inhibitor, including a PDX model of c-MET-altered KRASG12C NSCLC. Our results suggest that the combination of ABN401 and KRAS inhibitor could be an alternative treatment option for c-MET-altered KRASG12C NSCLC patients. Citation Format: Saehyung Lee, Sunghwan Cho, Na Young Kim, Rajasekaran Nirmal, Kyung Eui Park, Jun Young Choi. Synergistic anti-tumor effect of ABN401 in combination with KRAS inhibitor in a c-MET-altered KRASG12C non-small cell lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 382.
Abstract 3533: Zebrafish <i>her3</i> knockout impacts developmental and rhabdomyosarcoma-related gene signatures
Authors: Matthew R. Kent, Delia Calderon, Katherine M. Silvius, Jack P. Kucinski, Collette A. LaVigne, Matthew V. Cannon, Genevieve C. Kendall
Journal: Cancer Research (2023)

Abstract HES3 is a basic helix-loop-helix transcription factor that regulates neural stem cell renewal during development. HES3 overexpression is predictive of reduced overall survival in patients with fusion-positive rhabdomyosarcoma, a pediatric cancer that resembles immature and undifferentiated skeletal muscle and is most commonly driven by the fusion-oncogene PAX3-FOXO1. However, the mechanisms of HES3 cooperation in PAX3-FOXO1 driven rhabdomyosarcoma are unclear and are likely related to her3/HES3’s role in neurogenesis. To investigate HES3’s function during development, we generated a zebrafish CRISPR/Cas9 null mutation of her3, the zebrafish ortholog of HES3. Phenotypic characterization revealed that her3 null mutation is not embryonic lethal as they are present at expected Mendelian ratios. We observed a temporary growth delay her3 zebrafish null mutants and, rarely, eye defects in adults. Transcriptomic analysis of her3 null mutant embryos showed early dysregulation of a known downstream target, neurog1 and downregulation of genes involved in organ development, such as pctp and grinab, while genes pointing toward a terminal differentiation state, such as tmod, are upregulated. Differentially expressed genes in her3 null mutant embryos are enriched for HOX and SOX10 motifs, suggesting these may be key genes involved during HES3 dysregulation. Several cancer-related gene pathways are impacted, including the inhibition of matrix metalloproteinases and the tumor microenvironment pathway. To complement our zebrafish model, we are developing a double-inducible cell line model consisting of a tetracycline-inducible HES3 and a cumate-inducible PAX3-FOXO1 to further investigate the hypothesized cooperation between her3/HES3 and PAX3-FOXO1 in fusion-positive rhabdomyosarcoma. These two systems will allow us to elucidate conserved mechanisms of cooperation between HES3 and PAX3-FOXO1, and identify new therapeutic opportunities for children with fusion-driven rhabdomyosarcoma. Citation Format: Matthew R. Kent, Delia Calderon, Katherine M. Silvius, Jack P. Kucinski, Collette A. LaVigne, Matthew V. Cannon, Genevieve C. Kendall. Zebrafish her3 knockout impacts developmental and rhabdomyosarcoma-related gene signatures. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3533.
Abstract 2233: Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors
Authors: Melissa Soucy, Nick Renzette, Xinming Zhuo, Prasanti Nuni, Kristi Herlth, Kevin Kelly, Gregory Omerza, Lei Li
Journal: Cancer Research (2023)

Abstract Current cIMPACT-NOW and WHO guidelines state that the accurate diagnosis of many central nervous system (CNS) tumors must not only incorporate traditional histological findings but also include additional molecular data derived from sequence and methylation profiling techniques. To address this clinical need, our group has adapted and clinically validated the CNS tumor classifier that was pioneered and developed by the German Cancer Research Network (DKFZ) and University Hospital Heidelberg for both adult and pediatric CNS tumors. The classifier analyzes whole genome methylation data derived from the Illumina EPIC array system with a machine learning algorithm trained on a large reference set to provide a tumor family and class (a more granular classification than family) along with calibrated scores to aid in determining confidence in the assigned classifications. Around this core algorithm, we have generated a computational and reporting pipeline to generate a mid-throughput clinical diagnostic assay. We have validated this assay using a combination of adult and pediatric CNS tumor samples and have established reliable run-level and sample-level quality control metrics with empirically defined thresholds. With these thresholds, approximately 90% of samples with a neoplastic content of 70% or greater were “classifiable”, such that a result could be returned by the CNS tumor diagnostic assay. The performance of the assay was exceptional, with a sensitivity, specificity and accuracy each greater than 98% as determined with a validation sample set of 105 specimens. Further, 4 discordant calls between the original diagnosis and the output of the new methylation-based diagnostic were identified and underwent further histopathologic review. This additional analysis led to the re-classification of 2 specimens due to molecular analysis, highlighting the clinical utility of the assay. The new assay is currently offered for clinical testing under the name JAX OncoMethyl ArrayTM and addresses a clear need in the field of CNS tumor diagnostics. Citation Format: Melissa Soucy, Nick Renzette, Xinming Zhuo, Prasanti Nuni, Kristi Herlth, Kevin Kelly, Gregory Omerza, Lei Li. Clinical validation of a methylation array-based diagnostic assay for improved classification of CNS tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2233.
Abstract 3070: Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer
Authors: Bobae Park, Katarzyna Knapczyk-Stwora, Yaguang Liu, Chung S. Song, Bandana Chatterjee
Journal: Cancer Research (2023)

Abstract Advanced prostate cancer is a heterogeneous disease driven by diverse genetic alterations, with metastasis and lethal progression as the inevitable outcome. We observed that a subset of clinical primary prostate cancer is markedly reduced for SULT2B1b (SULT2B) sulfotransferase, which is an oxysterol-sulfating enzyme. Metastasized castration-resistant prostate cancer (CRPC) uniformly lacks SULT2B. Oxysterols are oxidized cholesterol metabolites and in agonist function, they activate liver X receptors (LXRα/β), which are members of the nuclear receptor family and regulators of lipogenesis, cholesterol homeostasis and immune functions. LXR signaling is enzymatically inhibited by SULT2B activity since sulfated oxysterols are LXR-inert. We previously reported that genetic silencing of SULT2B led to escalated CRPC proliferation; enhanced xenograft tumor growth; increased cell migration, invasion; reduced stiffness, adhesiveness; and EMT activation. SULT2B-depleted CRPC cells showed robust upregulation of AKR1C3 aldo-keto reductase and AKR1C3-dependent activation of the ERK1/2 survival signal. AKR1C3 regulates intratumoral androgen biosynthesis, and it is known to be elevated in advanced prostate cancer. In the current study, we validate our previous result by showing that ectopic expression of SULT2B caused AKR1C3 reduction in CRPC cells. Mechanistically, we observed that enhanced AKR1C3 expression in SULT2B-depleted cells was prevented upon genetic or pharmacologic inactivation of LXR. In addition, ERRα, another non-steroid nuclear receptor, was reduced in LXR-inactivated cells and notably, AKR1C3 was reduced in CRPC cells upon ERRα degradation by an ERRα-selective PROTAC. The LXR dependence of ERRα and AKR1C3 expression was observed in both androgen receptor expressing and non-expressing CRPC cells. Conclusion &amp; Translational Significance: Above results reveal a novel LXR-ERRα-AKR1C3-ERK axis which is activated in SULT2B-deficient CRPC cells irrespective of the androgen receptor status of these cells. Notably, elevated ERRα portends poor prognosis for prostate cancer and cholesterol is an ERRα agonist. Considering that statin can diminish ERRα activity (PMID 26777690) and AKR1C3 inhibitors are in clinical trials, this novel axis revealed from our study may be actionable for the clinical interception of the progression in SULT2B-low advanced prostate cancer. Citation Format: Bobae Park, Katarzyna Knapczyk-Stwora, Yaguang Liu, Chung S. Song, Bandana Chatterjee. Leveraging oxysterol sulfation by SULT2B1b sulfotransferase and liver X receptor inactivation to suppress advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3070.